1-[aromatic-(lower-alkyl)]-4-(aromaticimino)-1, 4-dihydroquinolines and their preparation



3,075,98 l Patented Jan. 29, 1963 ice 3 075 981 l-AnoivrArrcmaven-Annuna-tnnomartc- IMING) 1,4 DIHYDROQUINQLINES AND THEIRPREPARATIGN Alexander R. Surrey, Albany, N.Y., assigner to terling DrugInc., New York, N.Y., a corporation of Delaware N Drawing. Filed Apr. 3,was, er. No. 726,655 17 Claims. (Ci. Zak-256.4

This invention relatse to compositions of matter of the class of basicquinoline derivatives, to their acid-addition salts, and to thepreparation of these compounds.

The invention here resides in a composition of matter selected from thegroup consisting of: (a) a 1,4-dihydroquinoline that is substituted byan aromatic-(lower-alkyl) radical at the l-position and by anaromatic-imino radical at the 4-position, and that can be furthersubstituted by from one to two other substituents selected from thegroup consisting of halo, lower-alkoxy, lower-alkylmercapto,lower-alkyl, nitro and trifiuoromethyl radicals at one of the normallyaromatic positions of the quinoline nucleus, and, optionally, by alower-alkyl substituent at the 2-position of the quinoline nucleus; and,(b) acid-addition salts thereof.

Among the compounds of my invention are those which in free base formare represented by the structural Formula I R N Y 'Ar I where Qrepresents H or from one to two substituents at positions 3, 5, 6, 7 and8 of the quinoline nucleus selected from the group consisting of halo,lower-alkoxy, loweralkylmer'capto, lower-alkyl, nitro andtrifluoromethyl radicals; Ar and Ar are each an aromatic radicalincluding phenyl, naphthyl, biphenylyl, thienyl, furyl, pyridyl andpyrimidyl radicals; R is H or a loWer-alkyl radical; and Y is alower-alkylene radical.

In the above general Formula I the quinoline nucleus can beunsubstituted at the positions other and 1 and 4 or it can besubstituted further at one to two of the normally aromatic positions ofthe quinoline ring, namely, 3, 5, 6, 7 or 8, by the substituents namedabove. When Q designates two substituents, they can be the same ordifferent and can be in any of said available aromatic positionsrelative to each other. The halo substituents can be chloro, bromo, iodoor fiuoro. The lower-alkoxy, loweralkylmercapto and lower-alkylsubstituents have preferably from one to siX carbon atoms and includes:methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, 2- butoxy,n-pentoxy, n-hexoxy and the like when loweralkoxy; methylmcrcapto,ethylmercapto, n-propylmercapto, isobutylmercapto, n-hexylmercapto andthe like when lower-alkylmercapto; and methyl, ethyl, n-propyl,isopropyl, n-butyl, n-hexyl and the like when lower-alkyl.

The quinoline nucleus can be further substituted at the 2-position by alower-alkyl radical represented above as R and illustrated by methyl,ethyl, n-propyl, isobutyl, nbutyl, n-hexyl and the like.

The lower-alkylene radical designated above as Y can have preferablyfrom one to four carbon atoms and is illustrated by The aromaticradicals designated above as Ar and Ar can be the same or different andpreferably stand for monocarbocyclic-aryl radicals having sixring-carbon atoms, i.e., aryl radicals of the benzene series. Thesepreferred embodiments thus include the unsubstituted-phenyl radical andphenyl radicals substituted by substituents including halo, nitro,lower-alkoxy, hydroxy, lower-alkyl, lower-alkylmercapto,lower-alkylsulfonyl, trifiuoromethyl, lower-alkylamino,di-(lower-alkyDamino, lower-acylamino, and the like. Thesubstituted-phenyl radicals have preferably from one to threesubstituents including those given above; and, furthermore, thesesubstituen'ts can be in any of the available positions of the phenylnucleus, and Where more than one substituent, they can bethe same ordifferent and they can be in any of the various position combinationsrelative to each other. Thus Ar and Ar when standing for preferredembodiments comprehend the unsubstituted-phenyl radical as well assubstituted-phenyl radicals illustrated by: nitrophenyl radicalsincluding 4-nitrophenyl, 3-nitrophenyl, Z-nitrophenyl, etc.;(lower-alkoxylated)-phenyl including B-ethoxyphem yl, Z-methoxyphenyl,2,4-dimethoxyphenyl, 2,4,6-trimethoxyphenyl, 3,4-diethoxyphenyl, etc.;(lower-alkylated)-phenyl including 4-methylphenyl 3-ethylphenyl, 2-methylphenyl, 2,4-dimethylphenyl, 3,4,5-trimethylphenyl,4-isopropylphenyl, etc.; halogenated-phenyl including 2- chlorophenyl,4-chlorophenyl, 2,4-dibromophenyl, 3-iodophenyl, 2,4-dichlorophenyl,3,4-dichl0rophenyl, 2,4,6-trichlorophenyl, 4-fluorophenyl, etc.; andother substitutedphenyl radicals including 3-trifluoromethylphenyl,4-methylmercaptophenyl, 4-methylsulfonylphenyl, 4-n-butylaminophenyl,4-hydroxyphenyl, 4-diethylaminophenyl, 2- ch1oro-4-ethoxyphenyl,4-acetylaminophenyl, and the like.

Particularly preferred embodiments of my invention are compounds of theabove Formula I and their acidaddition salts of Formula II where Q is ahalo radical, Ar is a halogenated-phenyl or (lower-alkoxylated)-phenylradical, R is H, Y is CH and Ar is a halogenated-phenyl radical.

Preferred embodiments are my compounds in the form of theiracid-addition salts, which can be represented by the general structuralFormula II where Q, Ar, R, Y and Ar have the means designated above andAn is an anion.

The anion designated above as An can be any anion and is preferably achemotherapeutically acceptable anion, for instance, chloride, bromide,iodide, sulfate, phosphate, sulfamate, benzenesulfonate,para-toluenesulfonate, methanesulfonate, ethanesulfonate, citrate,tartrate, and the like; the anion has no appreciable activity of its ownin the high dilutions at which the acid-addition salts as a whole areeffective. In particular, the anions appear to contribute nothing to thechemotherapeutic properties which inhere to the cation portion of thesubstituted-1,4-dihydroquinolines of the present invention. However,preferred compounds are those in which An is hailde, in particular,chloride, iodide or bromide, since these are derived from readilyavailable starting materials. By a chemotherapeutically acceptableanion, I mean any anion which is innocuous to the animal organism inchemotherapeutic doses of the acid-addition salt, so that beneficialphysiological. properties inherent in the cation 3 v, are not vitiatedby any possible side-effects ascribable to the anions; in other words,the latter do not substantially affect the chemotherapeutic propertiesinherent in the cations.

The acid-addition salts are prepared directly as described hereinafteror they are prepared from the free base either by dissolving the freebase in an aqueous alkanol solution containing the appropriate acid andisolating the salt by evaporating the solution, or by reacting the freebase and acid in an organic solvent, e.g., a lower alkanol, in whichcase the salt separates directly or can be obtained by concentration ofthe solution. Alternatively, the acid-addition salts can be prepared bytreating an acid-addition salt (Formula II) prepared directly as notedabove with an anion exchange resin saturated with the desired anion.Although chemotherapeutically acceptable salts are preferred, allacid-addition salts are within the scope of my invention. Allacid-addition salts are useful as sources of the free base form even ifthe particular salt per se is not desired as the final product, as forexample when the salt is formed only for purposes of purification oridentification, or when it is used as an intermediate in preparing achemotherapeutically acceptable salt by ion exchange procedures.

Concerning the structure of the acid-addition salts represented above asFormula II, the following considerations are presented. From chemicaland physical data it ap pears that structure II is actually a resonancehybrid whose main contributing structures are represented as follows asAz B:

Since my compounds in free base from (Formula I) are readily obtainedfrom their acid-addition salts by reaction with an acid-acceptor, as"shown below, and since they are readily reconverted into theiracid-addition salts by treatment with an acid, "I prefer to representthe acid salt form by Formula II. -As an illustration, I prefer torepresent the hydrochloride salt of 7-chl0ro-l-(2-chlorobenzyl)-4-(4-chlorophenylimino)-l,4-dihydroquinoline by the following structuralFormula Ha:

Alternatively, this compound can be named 7-ch1oro-l-(2- chlorobenzyl)--4-(4-chlorophenylamino)quinolinium chloride or7-chloro-4-(4-chlorophenylamino) quinoline 2* chlorobenzochloride andcan be represented by the structural Formula 111):

g-Q l l Thus, it is to be understood that although I prefer to representthe acid-addition salt form of my compounds by the structural formuladesignated above as 11, i.e., as an acid-addition salt of a1-[aromatic-(lower-alkyl)1-4- (aromatic-imino)-1,4-dihydroquinoline,this 4-imino-1,4- dihydroquinoline structure actually represents onlyone of the contributing members of a resonance hybrid; and, further, itis to be understood that the salt form of my invention comprehends notonly this 4-imino-l,4-dihydroquinoline structure (as specificallyillustrated above as Ila) but also other contributing members of theresonance hybrid including thel-[aromatic-(lower-alkyl)1:4-(aromatic-amino)-quiuoliniurn saltstructure (as specifically illustrated above as 1112).

The compounds of Formula II are conveniently prepared by reacting thecorresponding 4-(aromatic-amino)- quinoline having the Formula 111ArY-An, where Ar, Y and An have the meanings given above, and if thecompounds of Formula I are 1 desired, then reacting the resultingacid-addition salt of the l[aromatic-(lower-alkyl)]-4-(aromatic-imino)-l,4- dihydroquinoline salt(Formula II above) with an acidacceptor to yield the product in freebase form (Formula 1). Thus, the reaction of7-chloro-4-(-chlorophenylamino)quinoline with 4-chlorobenzyl chlorideyields the hydrochloride of7-chloro-1-(4-chlorobenzyl)-4-(3-chlorophenylimino)-l,4-dihydroquinolinewhich when treated with an acid-acceptor yields7-chloro-l-(4-ehlorobenzyl)- 4- 3-chlorophenylimino-l,4-dihydroquinoline. The step of reacting the4-(aromatic-arnino)-quinoline (Formula 111) with the ester Ar--YAn iscarried out preferably by heating the reactants between about 50 C. and150 C., a particularly preferred range being between about C. and C. Thereaction can be run below 50 C., but it takes longer. The reaction iscarried out preferably in an organic solvent which is inert under theconditions of the reaction as for example, acetonitrile, acetone,ethanol, 2-propanol, and the like. When an inert solvent is used, theproduct usually separates from solution upon cooling, or can be obtainedby concentration of the solution. The reaction takes place most readilywith aromatic-(lower-alkyl) esters Ar-Y-An where An is the anion of astrong inorganic acid or an organic sulfonic acid. .T he chloride,bromide or iodide are preferred because of the more ready availabilityof the requisite aromatic-(lower-alkyl) halides. Compounds where theanion An is other than halogen or anions of strong acids can be preparedby reacting the free base form of my compounds having Formula I with theappropriate acid according to the procedure described above.

The step of reacting the acid-addition salt of the l-[aromatic(lower-alkyl)]- 4 (aromatic-imino)!1,4-dihydro quinoline (Formula II)with an acid-acceptor is carried out at room temperature or by warning,if necessary. The reaction can be carried out in an aqueous or organicsolvent; however, it is preferably carried out in an organic solventinert under the conditions of the reaction as for example, anhydrousmethanol, ethanol, and the like. The purpose of the acid-acceptor is totake up the hydrogen halide (or HAn) which is split out during thecourse of the reaction. The acid-acceptor is a basic substance whichpreferably forms freely water-soluble by-products easily separable fromthe product of the reaction, including for example, sodium hydroxide,potassium hydroxide, sodium carbonate, potassium carbonate, sodiumacetate, sodium alkoxides, potassium alkoxides, sodium amide, and thelike.

The compounds of Formulas I and H can also be prepared by reacting thecorresponding 4-haloquinolinium halide having the Formula IV ArY Anwhere Q, R, Y and Ar have the meanings designated above, An is a halideion and X is a chloro, bromo or iodo radical, with an aromatic-amine ofthe formula Ar'-NH and reacting the resulting HAn acid-addition salt(Formula II) with an acid-acceptor to yield the product in free baseform (Formula 1). Thus, the reaction of7-bromo-1-(2-chloro-4-ethoxyberzyl)-4-iodiquinolinium iodide with4-n-butoxyphenylamine (i.e., para-nbutoxyaniline) yields the hydroidideof 7-br0rn0-4-(4-nbutoxyphenylimino)-1-(2-chloro 4 ethoxybenzyl)-1,4-dihydroquinoline; and, the corresponding compound in free base form isobtained by treating the hydroiodide salt with an acid-acceptor asdescribed above.

The reaction of the 4-haloquinolinium halide (Formula IV) with anaromatic-amine Ar'NI-I is carried out preferably by heating thereactants at a temperature between about 50 C. and 150 C., preferablybetween about 75 and 125 C.; the reaction can be run at roomtemperature, but it takes longer. The reaction is preferably carried outin an organic solvent which is inert under the conditions of thereaction as for example, ethanol, and the like. If an inert solvent isused, the product usually separates from solution upon cooling, or canbe obtained by concentration of the solution.

Evaluation or" the l-(aromatic-alkyl)-4-arornatic-imino-1,4-dihydroquinolines and salts by standard test pro cedures has shownthat they have useful chemotherapeutic properties, in particular,amebacidal activity as determined in hamsters.

The following examples will further illustrate the invention without,however, limitin it thereto.

EXAMPLE 1 A. 4-(Ar0matic-Amino) -Quinlines These intermediate compoundsare generally known and are prepared by reacting an aromatic-amine witha 4-haloquinoline, as illustrated by the following synthesis of7-chloro-4- (2,4-dichlorophenylamino) quinoline;

A mixture of 32 g. of 4,7-dichloroquinoline and 26 g. of2,4-dichloroaniline was heated on a steam bath for about fifteen hours.The reaction mixture was dissolved in refluxing ethanol and the ethanolsolution was chilled in a refrigerator. The precipitate was collectedand dried at 70 C. for 20 mm. for about eighteen hours to yield 43.5 g.(76% yield) of 7-chloro-4-(2,4-dichlorophenylamino)quinoline in the formof its hydrochloride salt, MP. 274.0-278.6 C. (corn).

13 Analysis-Called. for C H CI N HCI: Cl,' 9.84; N,

7.78. Found: Cl, 9.55; N, 7.73.

ther new 4-(aromatic-amino)quinolines that were prepared andcharacterized following the foregoing procedure are the following:7-chloro-4-(2-chlorophenylamino)quinoline, MP. 151152 C.[Analysis.-Calcd. for C H CI N N, 4.85. Found: N, 4.87]; 7-chloro-4-('3-pyridylamino)quinoline, MP. 1S5.8189.0 C. (corr.) [Analysis.-Calcd.for C l-l ClN Cl, 13.88; N, 10.94; Found: Cl, 13.86; N, 10.82];7-chloro-4-(2-pyridylamino)quinoline, MP. l71.6173.8 C. (corr.)[Analysis.-Calcd. fOI C14H1QC1N3I C1, NAP, 10.90. Found: Cl, 14.01; N11.61] and HCl salt, MP. 308- 310 C. with decomposition;7-chloro-4-(Z-pyrimiclylamino) quinoline, MP. 213.6216.2 C. (corn)[Analysis.-Calcd. for C H CINO C1, 13.82; N, 21.82. Found: Cl, 13.83; N,21.98]; 7-chloro-4-pheny1aminoquinoline phosphate, MP. 263.5265 C. withdecomposition [Analysis.-Calcd. for C15IiuClN2.H3PD4I H PO 27.79; base,72.2. Found: H 1 0, 27.84; base,

72.6]; 7-chloro-4-(4-methexyphenylamino)quinoline hydrochloride, M.P.292294 C. [Analysis.Calcd. for C H clN OHCl: N, 8.72. Found: N, 8.94];and 7- chloro-4- 4-dimethylaminophenylamino) quinoline, M.P. 263265 C.with decomposition [Analysis.-Calcd. for C H ClN z Cl, 11.52; N, 13.65.Foundr'Cl, 11.66; N, 13.77].

Other 4-(aromatic-amino)-quinolines that can be prepared following theabove procedure for the preparation of7-chloro-4-(2,4-dichlorophenylamino)quinoline using the appropriate4-haloquinoline and aromatic-amine are:

4- 3-chlorophenylamino -6,7-dichloroquinoline;

7 -chloro-4- 3 ,4-dichlorophenylamino quinoline;

7 -bromo-4- (4-n-butoxyphenylamino quinoline 4- Z-methoxyphenylamino)-3-nitroquinoline;

5-chloro-4- (4-nitrophenylamino) quinoline;

4- (4-n-butylmercaptophenylamino) -6, S-dimethoxyquinoline;

8-n-butoxy-4- 4-n-butylsulfonylphenylamino quinoline;

6-n-hexoxy-4- 3 -tri1luoromethylphenylamino) quinoline;

8-isobutylmercapto-4- 4-n-propylaminophenyl quinoline;

7-chloro-4- 4-diethylaminophenylamino -6-methoxyquinoline;

4- 2-chloro-4-ethoxyphenylamino -7-trifiuoromethylquinoline;

7-1nethyl-4- (3 ,4,S-tribromophenylamino) quinoline;

7-iodo-4- 4-iodophenylamino) quinoline;

7-chloro-4- (4-fluorophenylamino -3-nitroquinoline;

7-chloro-4-( l-naphthylamino) quinoline;

4- 4-biphenylamino -7chloroqu'inoline;

7 -chloro-4- Z-thienylamino) quinoline;

7-chloro-4- (2-furylamino) quinoline;

7-chloro-4- 5 -chloro-2-pyridylamino) quinoline;

6,8-dichloro-4-phenylaminoquinoline;

7-chloro-4- 4-ethoxyphenylamino quinoline;

7-chloro-4- 4-chlorophenylamino) quinoline; and the like.

B. 4- (Aromatic-Imino) [A romatic- (Lower-A lkyl) ,4- HydroquinolinesThe preparation of these compounds by reacting a 4-(aromatic-amino)-quinoline with an aromatic-(loweralkyl) ester Ar-Y-Anis illustrated by the following preparation of7-chloro-1-(2-chlorobenzyl-4-( l-chlorophenylimino)-l,4-dihydroquinolinehydrochloride and corresponding base:

A solution containing 14.5 g. of7-chloro-4-(4-chlorophenylamino)quinoline, 32 g. of 2-chlorobenzylchloride and 205) cc. of acetonitrile was refluxed for eighteen hourswith stirring. The reaction mixture was allowedto cool and the resultingprecipitate was collected and recrystallized twice from ethanol to yield8.6 g. (35.5% yield) of 7-chloro-l-(Z-chlorobenzyl) 4(4-chlorophenylimino)- 1,4-dihydroquinoline hydrochloride, M.P.288.6-293.6 C. (corn),

Analysis.-Calcd. for C H Cl N HCl: Cl, 31.51; N, 6.22. Found: Cl, 31.71;N, 6.15.

Alternatively, as discussed hereinabove, 7-chloro-1-(2- chlorobenzyl)-4-(4 chlorophenylimino) 1,4 dihydroquinoline hydrochloride can becalled 7-cnloro-1-(2- chlorobenzyl) 4 (4 chlorophenylamino)quinoliniumchloride.

7-chloro-1 (2 chlorobenzyl) 4 (4chlorophenylirnino)-1,4-dihydroquinoline hydrochloride is converted intoits free base form, i.e., '7-ch1oro-1,(2-chlorobenzyl)-4-(4-chlorophenylimino) 1,4 dihydroquinoline, by reaction of thehydrochloride with an acid-acceptor according to the procedure given inExample 24(8) for the conversion of 7-chloro-1-(2-chlorobenzyl)-4 (4methoxyphenylimino)-l,4-dihydroquinoline hydrochloride into itscorresponding free base by reaction with aqueous sodium hydroxidesolution.

Other 4-(aromatic-i1m'n0)-1-[aromatic (lowepaikyl) 1,4-dihydroquinolinesthat can be prepared following the above procedure using the appropriate4-(aromaticamino)-quinoline and aromatic-(loWer-alkyl) ester of a strongacid include those given in Examples 2-23 inclusive.

EXAMPLE 2 1-benZyl-4 (3 chlorophenylimino) 6,7 dichloro-1,4-dihydroquinoline hydrobromide using4-(3-chlorophenylamino)-6,7-dichloroquinoline and benzyl bromide.

EXAMPLE 3 7-chloro-4(3,4-dichlorophenylirnino)-1 (2methoxybenzyl)-2-methyl 1,4 dihydroquinoline hydrochloride using7-ch1oro-4-(3,4-dichlorophenylamino) 2 methylquinoline and2-methoxybenzy1 chloride.

EXAMPLE 4 7 bromo 4 (4 n butoxyphenylimino) 1 [2- (2,4-dimethoxyphenyDethyl] 1,4 dihydroquinoline hydrobromide using 7 brorno 4(4 n butoxyphenylamino)quinoline and 2-(2,4-dirnethoxyphenyl)ethylbromide.

EXAMPLE 5 1-(2,4-dibrornobenzyl)-4 (2 methoxyphenylimino)- 3 ni-tro 1,4dihydroquinoline hydrobromide using 4-(Z-methoxyphenylamino)-3-nitroquinoline and 2,4dibromobenzyl bromide.

EXAMPLE 6 5 chloro 1 (2 chloro 4 methoXybenzyl)-4-(4- nitrophenylimino)1,4 dihydroquinoline hydrochloride using5-chloro-4-(4-nitrophenylamino)quinoline and 2- chloro-4-methoxybenzylchloride.

EXAMPLE 7 4 (4 n butylrnercaptophenylirnino) 1 [4 (4-chlorophenyl)-butyl] 6,8 dimethoxy 1,4 dihydroquinoline hydrochlorideusing 4-(4-n-butylmercaptophenylamino)-6,8-dimethoxyquinoline and4-(4-chlorophenyl)-butyl chloride.

EXAMPLE 8 8 n butoxy 4 (4 nbutylsulfonylphenylimino)- 1-(2,4,6trichlorobenzyl) 1,4 dihydroquinoline hydrochloride using8-n-butoxy-4-(4 n butylsulfonylphenylamino)quinoline and2,4,6-trichlorobenzyl chloride.

EXAMPLE 9 6-n-hexoxy-1-(4-nitrobenzyl) 4 (3trifluorornethylphenylimino)1,4-dihydroquinoline hydrobromide using 6 nhexoxy 4 (3 trifluoromethylphenylamino)- quinoline and 4-nitrobenzy1bromide.

EXAMPLE 10 8 isobutyhnercapto -4 (4 npropylaminophenylimino)-1-(3-trifluoromethylbenzyl)-1,4 dihydroquinoline8 hydrochloride using 8-isobutylmercapto-4-(4 npropylaminophenylarnino)quinoline and 3-trifiuoromethylbenzyl chloride.

EXAMPLE 1 l 7 chloro 4 (4 diethylaminophenylimino) 6- methoxy 1 (4npropylmercaptobenzyl) 1,4 dih droquinoline hydrochloride using7-chloro-4-(4-diethylaminophenylarnino) -6-methoxyyquinoline and4-n-propylmercaptobenzyi chloride.

EXAMELE 12 4-(2 chloro 4 ethoxyphenylimino) 1-(4-n-propylsulfonylbcnzyl)7 trifluoromethyl-1,4-dihydroquinoline hydrochloride using 4 (2 chloro-4:thoxyphenlamino)- '7-trifluoromethylquinoline and4-n-propylsulfonylbenzyl chloride.

EXAMPLE 13 7-methoyl-1-(3 phenylpropyl) 4 (3,4,5 tribromd phenylimino)-1,4-dihydroquin0line hydrobromide using 7- methyl-4-(3,4,5tribromophenylamino)quinoline and 3- phenylpropyl bromide.

EXAMPLE 14 1-(4-biphenylylmethyl) 7 iodo 4 (4iodophcnylimino)-l,4-dihydroquinoline hydrobromide using 7-iodo-4-(4-iodophenylamino) -quinoline and 4-biphenylylmethyl bromide.

EXAMPLE 15 1 (4 n butylaminobenzyl) 7chloro-4-(4-fluorophenylirnino)-3-nitro-1,4-dil1ydroquinolinehydrobromide using 7 chloro 4 (4-fluorophenylamino)-3-nitroquinoline and4-n-butylaminobenzyl bromide.

EXAMPLE 16 7 chloro 1 (2 chlorobenzyl) 4 (1 naphthylimino) 1,4dihydroquinoline hydrochloride using 7-chloro-4-(1-naphthy1ami11o)quinoline and 2-chlorobenzyl chloride.

EXAMPLE l7 4 (4 biphenylylimino) 7 chloro 1(4-iodobenzyl)-1,4-dihydroquinoliue hydriodide using4-(4-biphenylylarnino) -7-chloroquinoline and 4-iodobenzyl iodide.

EXAMPLE 18 7-chloro-4 (2 thienylimino) 1 (Z-thienyImethyD-1,4-dihydroquinoline hydrochloride using 7-chloro-4-(2-thienylamino)-quinoline and Z-thienylmethyl chloride.

EXAMPLE 19 7 chloro 1 (2 chlorobenzyl) 4 (2 furylimino)-1,4-dihydroquinoline hydrochloride using 7-chloro-4-(2-furylarnino)quinoline and 2-chlorobenzyl chloride.

EXAMPLE 20 7 chloro 4 (5 chloro 2 pyridylirnino)- 1 (2-furylmethyl)-l,4-clihydroquinoline hydrochloride using 7-chloro-4-(5-chloro-2-pyridylamino)quinoline and 2-furylmethyl chloride.

EXAMPLE 21 6,8-dichloro-1-(2 naphthylrnethyl) 4 phenylimino-1,4-dihydroquinoline hydrochloride using 6,8-dichloro-4-phenylaminoquinoline and Z-naphthylrnethyl chloride.

EXAMPLE 22 7 chloro 4 (4 ethoxyphenylirnino) 1-(2-pyridylmethyl) 1,4dihydroquinoline hydrochloride using 7chloro-4-(4-ethoxyphenylamino)quinoline and 2-pyridylmethyl chloride.

EXAMPLE 23 7-eh1oro 4 (4-chlorophenylimino) 1(Z-pyrimidylmethyl)-1,4-dihydroquinoline hydrochloride using 7-chloro-4-(4-chlorophenylamino)quinoline and 2-pyrimidylmethyl chloride.

The compounds of Examples 2-23 inclusive are converted into their freebase form by reaction with an acid-acceptor according to the proceduregiven in Example 24(B) for the conversion of 7-chloro-1-(2-ch1oro-'benzyl)-4-(4 methoxyphenylimino) 1,4 dihydroquinoline hydriodide intoits corresponding free base by reaction with aqueous sodium hydroxidesolution.

EXAMPLE 24 A. 1-[Ai0matic=(L0wer-Alkyl) ]-4-Haloquin0linium Halides Thepreparation of these intermediates is illustrated by the followingpreparation of 7-chloro-1-(2-chlorobenzyl) -4-iodoquinolinium iodide:

A reaction mixture containing 80 g. of 4,7-dichloroquinollne, 128 g. of2-chlorobenzyl chloride, 177 g. of sodium iodide and 1200 cc. ofacetone'was refluxed for twenty-four hours with stirring. The reactionmixture was allowed to cool; and the resulting precipitate was collectedand washed successively with acetone, water and acetone. There was thusobtained 130 g. (60% yield) of7-chloro-1-(2-chlorobenzyl)-4-iodoquinolinium iodide, M.P. 208-209 C.(uncorr.).

Following the above procedure using an equivalent quantity of4,5-dichloroquinoline in place of 4,7-dichlorquinoline, the productobtained was S-chloro-l-(Z-chlorobenzyl)-4-iodoquinolinium iodide, M.P.201202 C. with decomposition.

Analysis-Called. for C H Cl INl-II: C, 35.45; H, 2.04; I-, 23.42. Found:C, 35.28; H, 2.30; I, 25.6.

Following the above procedure in the absence of sodium iodide,4,7-dich1oroquinoline and 2-chlorobenzyl chloride react to forml-(2-chlorobenzyl)-4,7-dichloroquinc-llnium chloride; use of4,7-di-bromoquinoline and 2-bromobenzyl bromide in the abence of so iumiodfde yields 1-(2-bromobenzyl)-4,7-dibromoquinolinium bromide.

Other 1-[aromatic-(lower-alkyl)] 4 haloquinolinium iodides that can beprepared following the above procedure using the appropriate4-haloquinoline, aromatic- (lower-alkyl) halide and sodium iodideinclude: 3,7-dichloro-4-iodo-1-(3-nitrcbenzyl)quinolinium iodide using3,4,7-trichloroquinoline, 3-nitrobenzyl chloride and sodium iodide;7-bromo-1-(2,4-dirnethoxybenzyl)-4-iodoquinoliniurn iodide using4,7-d'bromoquinoline, 2,4-dimethoxybenzyl bromide and sod'um iodide;8-ch1oro-4 iodo- 1-(2,4,6-trimethoxybenzyl)quinolinium iodide using 4,8-dichloroquinoline, 2,4,6-trimetho-xybenzyl chloride and sodium iodide;1-(3-ethylbenzyl)-4-iodo-7-trifiuoromethylquinol'nium iodide using4-iodo-7-trifiuoromethylquinoline, 3-ethylbenzyl chloride and sodiumiodide; 4-iodo- 7-rnethylmercapto 1 (2 -methylmercaptobenzyl)quincliniumiodide using 4-chloro-7-rnethylmercaptoquinoline,2-methylmercaptobenzylchloride and sodium iodide; 7-chloro-l-[2-(4-chlorophenyl)ethyl] 4 iodo 2 methylquinolinium iodideusing 4,7-dichloro2-methylquinoline, 2-(4-chlorophenyl)ethyl chlorideand sodium iodide; 1- (4-biphenylylmethyl)-7-chloro-4-iodoquinoliniumiodide using 4,7-dichloroquin0line, 4-bipheny1ylrnethyl chloride andsodium iodide; 7-chloro-4-iodo-1-(2-thienylmethyi)quinolinium iodideusing 4,7-dichloroquinoline, Z-thienylrnethyl chloride and sodiumiodide; 7-chloro- 1-(2-furylmethy1)-4-iodoquinolinium iodide using 4,7-dichloroquinoline, Z-furylmethyl chloride and sodium iodide; 7-chloro 4iodo-1-(3-pyridylrnethyl) quinoliniurn iodide using4,7-dichloroquinoliue, 3-pyridylmethyl chloride and sodium iodide;7-chloro-4-iodo-l-(2-pyrirnidy1- m thyDquinoIinium iodide using4,7-dichloroquinoline, 2-pyrimidylmethyl chloride and sodium iodide; andthe like.

ill B. 4 (Ar0matic-Imin0)-1-[Aromatic-(Lower-Alkyl)1,4-Dihydr0quin0lines lected, yielding 5.0 g. of7-chloro-1-(2-chlorcbenzyl)-4- (4 methoxyphenylimino) 1,4dihydroquinoline hydriodide. The hydriodide salt was dissolved inethanol and treated w th 10% aqueous sodium hydroxide solu ion toprecipitate the imino base, which crystallized on addition of water withcooling. The solid product was recrystallized from ethanol to give 2.9g. (71% yield) of 7-chlorol-(2-chlorobenzyl) 4(4-methoxyphenylirnino)-1,4-dihydroquinoline, M.P.- -145.0-148.0 C.(corn).

Analysis.Calcd. for CggHmClzNzOi Cl, 17.32; N, 6.86. Fcund: Cl, 17.42;N, 6.59.

7-chloro-1-(2-chlorobenzy1) 4(4-methoxyphenylirnino)-1,4-dihydrcquino1ine is converted into itshydrochloride salt by treating it in isopropyl alcohol solution with asolution of hydrogen ch'oride in ethanol until the solution is acidic,cooling the solution, and collecting the precipitated hydrochloridesalt. By substitution of the hydrogen chloride in the preceding examplewith hydrogen bromide, phosphoric acid, sulfuric acid, tartaric acid,sul amic acid or methanesulfonic a:id, there can be obtained7-chloro-1-(2-chlorobenzyl) -4-(4-methoxyphenylimino)-l,4-dihydroquinoline hydrobrornide, phosphate,sulfate, tartrate, sulfarnate or methanesulfo-nate, respectively.

Following the above procedure using1-(2-chlorobenzyl)-4,7-dchoroquinolinium chloride in place of 7- chloro1 (2-chlorobenzyl) 4 iodoquinolinium iodide, there is obtained directly7-chloro-1-(2-chlorobenzyl)-4- (4 methoxyphenylimino) 1,4dihydroquinoline hydrochloride; using 4-bromo-'7-chloro-1-(2-chlorobenzyl)quinoliniurn bromide, there is obtained7-chloro-1-(2-chlorobenzyl)-4-(4 methoxyphenylirnino) 1,4dihydroquinoline hydrobromide.

Other 4-(aromatic-imino)-l-[ aromatic-(lower-alkyl)1,4-dihydroquinolines that can be prepared following the above procedurefor the preparation of 7-chloro-1-(2- chlorobenzyl) 4 (4methoxyphenylimino)-1,4-dihydroquinoline using the appropriatel-[aromatic-(loweralkyl)]-4-iodoquinolinium iodide and aromatic-amineinclude those given in Examples 25-35 inclusive.

EXAMPLE 25 3,7-dichloro- 4 (Z-naphthylimino)-1-(3-nitrobenzyl)-1,4-dihydroquinoline using3,7-dI'chloro-4-iodo-l-(3-nitrobenzyl)quinolinium iodide andZ-naphthylamine.

EXAMPLE 26 4-(4-biphenylylimino)-7-bromo-1-(2,4dimethoxybenzyl)-1,4-dihydroquinoline using7-bromo-1-(2,4-dimethoxybenzyl)-4-iodoquinolinium iodide and4-biphenylylarnine. 7

EXAMPLE 27 8-chl0r0-4-(Z-thienylimino)-1 (2,4,6trimethoxybenzyl)-1,4-dihydroquino1ine using 8-chloro-4-iodo-l-(2,4,6-trimethoxybenzyl)quinolinium iodide and Z-thienylamine. EXAMPLE 28.fiuorornethylquinolinium iodide and 2- furylamine.

l1 EXAMPLE 29 7-methylmercapto-1-(2 methylmercaptobenzyl)-4-(2-pyridylimino)-1,4-dihydroquinoline using 4-iodo-7-methylmercapto 1 (2methylmercaptobenzyl)quinolinium iodide and Z-aminopyridine.

EXAMPLE 30 7-chloro-1-[2-(4-chlorophenyl)ethyl] 2 methyl-4(2-pyrirnidylimino)-l,4-dihydroquinoline using 7-chloro-1-[2-(4-chlorophenyl)ethy11-4-iodo -'2 methylquinolinium iodide and2-aminopyrimidine.

EXAMPLE 3 l EXAMPLE 3 3'l-chloro-l-(Z-furylmethyl)-4-(2-iodophenylimino)-1,4- dihydroquinolineusing 7 chloro-l (2 furylrnethy1)-4- iodoquinolinium iodide andortho-iodoaniline.

EXAMPLE 34 7-chloro-4-(Z-nitrophenylimino) -1-( 3 pyridylmethyl)1,4-dihydroquinoline using7-ehloro-4-iodo-1-(3-pyridylmethyl)quinoliniurn iodide andortho-nitroaniline.

EXAMPLE 3S4-(4-chlorophenylimino)-1-(2,4-dichlorobenzyl)-1,4-dihydroquinoline andits hydriodide can be obtained following the procedure described inExample 24(B) using 1-(2,4 dichlorobenzyl) 4 iodoquinoliniurn iodide andpara-chloroaniline.

EXAMPLE 37 7-chloro-l-(2-chlorobenzyl)-4-(4 methylphenylirnino)-1,4-dihydroquinoline hydrochloride can be obtained following theprocedure described in Example 24(B) using1-(2-chlorobenzyl)-4,7-dichloroquinolinium chloride andpara-methylaniline.

EXAMPLE 3 8 7-bromo-1-(2 brornobenzyl) 4 (4methoxyphenylirnino)-l,4-dihydroquinoline hydrobromide can be obtainedfollowing the procedure described in Example 24(3) usingl-(2-brornobenzyl)-4,7-dibrornoquinolinium bromide and para-anisidine.

EXAMPLE 39 7-Chl0r0-1-(Z-Chlorobenzyl) 4 (2,4Dichlorophenylimino)-1,4-Diltydroquinline Hydrochloride Following theprocedure described in Example 1(B) using 9 g. of7-chloro-4-(2,4-dichlorophenylamino)quinoline, 18 g. of 2-chlorobenzylchloride and 290 cc. of acetonitrile,

there was obtained 5.8 g. of 7-chloro-1-(2-chlorooenzyl)-4-(2,4-dichlorophenylimino)-1,4 dihydroquinolinehydrochloride, M.P. l65.6-l72.4 C. (corn) when recrystallized twice fromethanol.

Analysis.Calcd. for C H Cl N HCl: Cl, 7.32; N, 5.77. Found: Cl, 7.16; N,5.63.

7-chloro-1,-(2-chlorobenzyl)-4 (2,4dichlorophenylimino)-l,4-dihydroquinoline in free base form is obtainedfrom the hydrochloride by reaction with aqueous sodium hydroxidesolution following the procedure described above in Example 24(B).

EXAMPLE 40 7-Chl0r0-1-(Z-Chlorabenzyl) -4-(2 Chlorophenylimino)1,4-Dihydr0quinoline Hydrochloride This compound was prepared followingthe procedure described in Example 1(B) using 10 g. of 7-chloro-4-(2-chlorophenylamino)quinoline, 22.2 g. of 2-chlorobenzyl chloride and 200cc. of acetonitrile. There was thus obtained 7.9 g. of7-ch1oro-1-(2-chlorobenzyl)-4-(2-chlorophenylimino) 1,4 dihydroquinolinehydrochloride, M.P. 261.2-269.4 C. (corn) when recrystallized once fromethanol.

Analysis.-Calcd. for C H Cl N l-ICl: Cl, 31.51; N, 6.22. Found: Cl,31.83; N, 6.20.

7 -chloro-l-(Z-chlorobenzyl)-4-(2 chlorophenylimino)-1,4-dihyclroquinoline in free base form is obtained by reaction of thehydrochloride with aqueous sodium hydroxide solution according to theprocedure described in Example 24(B) EXAMPLE 41 7-Chlor0-1-(2-Chl0r0benzyl) -4-(4-Hydroxyphenylimino) -1,4-Dihydr0quinolineHydrochloride A mixture containing 5.4 g. of 7-chloro-1-(2-chlorobenzyl)4-iodoquinolinium iodide, 5.5 g. of para-aminophenol and 200 cc. ofethanol was heated. After the quinolinium iodide had dissolved, therewas obtained a clear red solution which was allowed to cool slowly toroom temperature. The product that separated was collected to give 3.1g. of 7-chloro-l-(2-chlorobenzyl)-4-(4- hydroxyphenylimino) 1,4dihydroquinoline hydriodide, M.P. 257-258" C. g

The above hydriodide salt was converted into the correspondinghydrochloride salt by dissolving it in ethanolwater with warming andpassing the resulting solution rapidly through 40 g. of an ion-exchangeresin saturated with chloride ions (such as Amberlite IRA-400ionexchange resin supplied by Rohm & Haas Co.). The orange filtrate wasthen slowly passed through another 40 g. portion of the ion-exchangeresin. The resulting orange solution was concentrated and the resultingyellow precipitate was collected and dried overnight at 60 C. at 1 mm.to yield 3 g. of 7-chloro-1-(2-chlorobenzyD-4-(4- hydroxyphenylimino)1,4 dihydroquinoline hydrochloride, M.P. 300 C. (corn).

Anqlysis.--Calcd. for C H cl N QHclz Cl, 8.22; N, 6.49. Found: Cl, 8.08;N, 6.19.

The hydrochloride salt is converted into the corresponding imino base,7-chloro-l-(2 chlorobenzyl) 4 (4hydroxyphenylimino)-1,4-dihydroquinoline, by treating an ethanolsolution of the salt with 10% aqueous sodium hydroxide solutionaccording to the procedure given in.

Example 24(8).

EXAMPLE 42 7-Chl0r0-1-(Z-Chlorobenzyl)-4-(2-Pyridylimino)-1,4-Dihydr0quln0line Analysis-Oiled. for C H CI N HI: N, 8.26; I, 24.85.Found: N, 8.18; I, 24.94.

Following the procedure described in Example 24(B) using 10.2 g. of7-chloro-1-(2-chlorobenzyl)-4-(2-pyridylimino)-l,4-dihydroquinolinehydriodide, 20 cc. of 35% aqueous sodium hydroxide solution and 200 cc.of methanol there was obtained 3.5 g. of7-chloro-l-(2-ehlorobenzyl)-4-(2-pyridylimino) 1,4 dihydroquinoline,M.P. 172.8-174.2 C. (corn) when recrystallized from isopropyl alcohol.

Analysis.-Calcd. for"C ;H Cl N Cl, 18.64; N, 11.02. Found: Cl, 18.66; N,11.22.

EXAMPLE 43 EXAMPLE 44 7-Clzlor0-I-(2-Clzlorobenzyl)-4-(2-Pyrimidylimino) 1,4-Dihydrquinoline This preparation was carriedout following the procedure described in Example 24(B) using 27.1 g. of7-chloro-1-(2-chlorobenzyl) 4 iodoquinoliniurn iodide, 14.2 g. ofZ-aminopyrirnidine and 200 cc. of isopropyl alcohol. There was firstobtained 7-chloro-1-(2-chlorobenzyl) -4-(2-pyrimidylimino)-1,4-dihydroquinoline hydriodide which was then converted into7-chloro-1-(2-chlorobenzyl)-4-(2-pyrimidylimino) -1,4dihydroquinoline,M.P. 214.82l9.4 C. (corr.)' when recrystallized once from isopropylalcOhol, once from ethanol and once from chloroformacetone.

Analysis.Calcd. for C H Cl N Cl, 18.60; N, 14.70. Found: C1, 1857; N,14.60.

EXAMPLE 45 7-Chl0r0-1-(2-C/z Iorobenzyl) -4- (4-Dimethylamin0-phenylimino)-1,4-Dihydr0quinolir1e This preparation was carried outfollowing the procedure described in Example 41 using 10 g. of 7-chloro-1-(2-chlorobenzyl)-4-iodoquinolinium iodide, 9.6 g. of4-dimethylaminoaniline hydrochloride, 2.22 g. of sodium hydroxide and 75cc. of ethanol. There was first obtained7-chloro-1-(Z-chlorobenzyl)-4-(4dimethylaminophenylimino)-1,4-dihydroquinoline hydriodide which was thenconverted into the corresponding hydrochloride salt by treatment with anion-exchange resin saturated with chloride ions as illustrated inExample 41. The hydrochloride salt was then dissolved in hot ethanol andthe ethanol solution was made strongly basic with aqueous sodiumhydroxide solution. The alkaline solution when cooled yielded aprecipitate which was recrystallized from benzene-n-hexane to yield 3.1g. of product, 7-chloro-l-(2-chlorobenzyl)-4-(4-dimethylaminophenylimino) 1,4 dihydroquinoline, M.P.206.4209.4 C. (corn).

AnaIysis.-Calcd. for C H Cl N Cl, 16.79; N, 9.95. Found: Cl, 16.66; N,9.89.

4-(aromatic-imino)-1-[aromatic lower-alkyl)] 1,4- dihydroquinolines andacid-addition salts of the foregoing examples when administered orallyto hamsters infected with Endamoeba cricetz' were found to completelyclear the animals at drug levels below 200 mg. per kg. of body weightper day. Some of the compounds, for instance,

14 7-chloro-1-(2-chlorobenzyl) -4-( 4 methoxyphenylimino)1,4-dihydroquinoline and 7-chloro l (2 chlorohenzyl)- 4-2-chlorophenylimino 1,4-dihydroquinoline hydrochloride, have ED valuesbelow 50 mg. per kg. per day, ED meaning the effective dose necessary toclear 50% of the hamsters of the amebic infection.

My new 4 (aromatic imino) 1 [aromatic(loweralkyl)]-1,4-dihydroquinolines and acid-addition salts are bestadministered orally in solid form with the. aid of'a carrier. Thus, thecompounds can be formulated in unit dosage form as tablets incombination with an adjuvant such as one or more of the following:calcium carbonate, starch, gelatin, talc, magnesium stearate, acacia,and the like; or, alternatively, they can be employed in capsule formeither alone or admixed with an adjuvant.- My compounds also can beadvantageously combined with other vameb'acides, such asN-(2,4-dichlorobenzyl)-N- (Z-hydroxyethyl)dichloroacetamide, whendesired. Illustrative of a tablet formulation of my compounds is oneweighing 660 mg. and containing 500 mg. of 7-chloro-1-(2-chlorobenzyl) 4(4-methoxyphenylimino) -1,4-dihydroquinoline, 25 mg. of calciumcarbonate asa diluent, 90 mg. of

.starch as a disintegrator, 30 mg. of gelatin as a binder and 15 mg. oftalc as a lubricant. Illustrative of a capsule formulation is onecontaining 500 mg. of. 7-chloro-1-(2-chlorobenzyl)-4-(2-chlorophenylimino)-1,4 dihydroquinolinehydrochloride, 40 mg. of starch and 10 mg. of talc. Other tablet andcapsule formulations can be made varying the quantities of adjuvants orusing other 4-(aromaticimino)-1-[aromatic-(lower alkyl)] 1,4dihydroquinolines or acid-addition salts as active amebacidalingredients.

I claim:

1. A composition of matter selected from the (group consisting of: (a)the 1-[aromatic-(lower-alkyl)]-4- (aromatic-imino) 1,4 dihydroquinolinehaving the formula I Y-Ar "tuted-phenyl having from one to threesubstit-uents seleoted from the group consisting of halo, nitro,loweralkoxy, hydroxy, lower-alkyl, lower-alkylmercapto,lower-alkylsulfonyl, trifiuoromethyl, lower-alkylamino,di-(l-ower-alkyl)amino and lower-acylamino, R is a member selected fromthe group consisting of H and lower alkyl, :and Y is loWer-alkylene;and, (b) acid-addition salts thereof.

2. The 1 aryl methyl-4-arylimino-7-halo-1,4-dihydroquinoline having theformula CHzAI where Q is halo, and A1 is halogenated-phenyl and A1" is(lower-alkoxylated)aphenyl.

where Q, Ar and R have the meanings l 3. Acid ad-dition salt of thecompound of the formula IfiL-Al" ll Q 111 CHzAI 1,4-dihydroquinoline.

10. 7-cl1loro-l-(Zchlorobenzyl)-4-(2 pyridylimino)-1,4-dihydroquinoline.

11. 7-chloro-1-(2-chlorobenzyl) 4 (2 pyrimidylimino)-1,4-dihydroquinoline.

12. A process for the preparation of the acid-addition salt of thel-[aromatic-(lower-alkyl)l-4-(aromaticimino)-1,4-dihydroquinoline havingthe formula where Q is selected fromthe group consisting of H and fromone to two substituents at positions 3, 5, 6, 7 and 8 of the quinolinenucleus selected from the group consisting of halo, lower-alkoxy,loweraalky-lmercapto, loweralkyl, nitro and trifiuoromethyl, Ar and Arare each selected from the group consisting of phenyl, naphthyl,biphenylyl, thienyl, furyl, pyrid-yl, pyrimidyl and substituted-pheny-lhaving from one to three substituents selected from the group consistingof halo, nitro, loweralkoxy, hydroxy, lower-alkyl, lower-alkylmercapto,lower-alkylsulfonyl, triiiuoro-methyl, lower-alkylamino,di-(lower-alkyl)amino and lower-acylamino, R is a member selected fromthe group consisting of H and loweralkyl, Y is loWer-alkylene and An isan anion of a strong acid, which comprises reacting the corresponding 4-(aromatic-amino)-quinoline having the formula IfH-Ar' already desig-Ar-Y-An.

the acid-addition mated, with an ester having the formula 13. A processfor the preparation of salt of the1-arylmethyl-4-arylimino-7-halo-1,4-dihydro-- quinoline having theformula HAn 16 where Q is halo, An is the anion of a strong acid, Ar andAr are each halogenated-phenyl, which comprises reacting thecorresponding 4-arylamino-7-haloquinoline with an ester having theformula ArCH -An.

14. A process for the preparation of a hydrohalide of the 1-[ar0rnatic-(lower-alkyl) -4-(arom-atic-imino) -1,4 d-ihydroquinolinehaving the formula HAn a R E i-Ar where Q is selected from the groupconsisting of H and from one to two substituents at positions 3, 5, 6,'7 and 8 of the quinoline nucleus selected from the group consisting ofhalo, lower-alkoxy, lower-alkylmeroapto, loweralkyl, nitro andtrifluoromethyl, Ar and Ar are each aromatic radicals selected from thegroup consisting of phenyl, naphthy-l, biphenylyl, thienyl, fu-ryl,pyridyl and pyrimidyl radicals, Risa member selected from the groupconsisting of H and lower-alkyl, Y is lower-alkylene and An is a halideion, which comprises reacting a 4-haloquinolinium halide having theformula of chloro, bromo and iodo, with an aromatic-amine having theformula Ar'NH 15. A process for the preparation of the compound havingthe formula CHzAr where Q is halo and Ar and Ar are eachmonocarbocyclic-aryl having six ring-carbon atoms, which comprisesreacting a 4-iodoquinolinium iodide having the formula with an aryla-mine having the formula Ar'-NH 16. A process for the preparation ofthe compound having the formula 18 where Q is halo, and A1" and Ar areeach halogenatedphenyl, which comprises reacting the correspondingacidaddition salt with an acid-acceptor.

References Cited in the file of this patent UNITED STATES PATENTSHaefiiger et a1. May 29, 1951 B-urckhalter June 22, 1954 OTHERREFERENCES Chemical Abstracts, vol. 24, pages 5753-5754 (1930); abstractof Mikhailenko et aL, 1. Russ Phys. Chem. Soc., vol. 61, pages 2267-77(1929).

Elderfield: Heterocyclic Compounds, v01. 4, pages 167-170, John Wileyand SO-ns (1952).

Gopalchari: Chem. Abstracts, v01. 49, p. 3967 (1955), citingcontribution of J. Sci. Ind. Research (India), 133 pp. 15-20 (1954).

Schock: Journal American Chem. Soc, vol. 79 (1957), pp. 1670-72.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No.3,075,981 January 29, 1963 Alexander R. Surrey 4 It is hereby certifiedthat error appears in the above numbered patent requiring correction andthat the said Letters Patent should read as corrected below.

Column 1, line 9, for "'relatse" read relates line 71, for "-CH(CH (CHCH read CH(CH )CH CH column 2, line 53, for "means" read meanings column4, lines 4 to 12, the upper portion of formula 1110 should appear asshown below instead of as in the patent:

NH Cl same column 4, line 47, for "4(-chlorophenyl-" read 4-(3-hlorophenylcolumn 5, line 2, for "warning" read warming lines 34 and35, for "iodiquinolinium" read iodoquinolinium line 36, for "hydroidide"read hydrlodlde line 39, for :"hydroipdide" read hydriodide same column-5, line 72, for "for", first occurrence, read at column 6, line 42, for"(4-n-propylaminophenyl)" read (4-n-propylaminophenylamino) line 63, for"(2-chlorobenzyl-4-X' read (2-chlorobenzyD-4- column 7, line 10, for "7'chloro-l,(2" read 7-ch1orol(2- column 8, line. 14,

for "(2 -chloro4ethoxyphenlamino) read (2chloro 4ethoxyphenylamin0) line19, for "7-met hoyl" read 7methyl column 12, line 5, for "7chl0ro-l,"read II a H 7-chloro-lcolumn 13, line 68, for C H Cl N read C H Cl Ncolumn 14, line 53, for "biphenyl" read biphenylyl column 15, lines 56to 60, the formula should appear as shown below instead of as in thepatent:

NH-Ar column l6, lines 9 to 15, the formula should appeara-s ehown belowlnstead of as in the patent:

HAn

ET-Ar R T Y-Ar Signed and sealed this 29th day of October 1963.

(SEAL) Attest:

ERNEST W. SWIDER EDWIN L, REYNOLDS Attesting Officer Acting Commissionerof Patents

1. A COMPOSITION OF MATTER SELECTED FROM THE GROUP CONSISTING OF: (A)THE 1- AROMATIC-(LOWER-ALKYL) !-4(AROMATIC - IMINO) - 1,4 -DIHYDROQUINOLINE HAVING THE FORMULA